In 2010, 18,600 adults and children were diagnosed with acute leukemias (ALL and AML) with 10,400 expected deaths (55%). Among acute leukemias, ALL and AML subtypes with an oncogenic tyrosine kinase have a particularly high frequency of relapse and overall poor outcome. For instance, median disease-free survival (DFS) for standard AML is 20 months compared to 4.6 months for patients with FLT3ITD AML. Likewise, DFS for standard risk ALL is at 23.8 months compared to 8.7 months for patients with Ph+ ALL carrying the BCR-ABL1 tyrosine kinase. While initial TKI therapy for patients with FLT3ITD AML and Ph+ ALL is initially successful, TKI fail to eradicate leukemia-initiating cells42 and the leukemias invariably relapses. Therefore, TKD-leukemias represent a frequent unsolved clinical problem. By contrast, the advent of potent TKI has transformed CML into a long-term condition. With 4,870 patients newly diagnosed in 2010, currently 24,800 patients live with CML in the US with a 5-year overall survival of >95%. However, also in CML, TKI fail to eradicate LIC, thus TKI-treatment for CML patients is typically life-long since measurable amounts of LIC persist in the bone marrow and CML re-emerges once TKI-treatment ceases. Since recent work has implicated leukemia initiating cells (LIC) in both initial drug-resistance and relapse of the disease, current therapy approaches need to focus on LIC eradication. Acute and chronic myeloid leukemias develop hierarchically from a phenotypically distinct stem cell population. However, recent work suggests that no hierarchically distinct stem cell population exists in B cell lineage ALL7. In the absence of a stem cell hierarchy, we hypothesize that B cell linage ALL have the ability to temporarily acquire stem cell capabilities, i.e. the ability to initiate leukema in xenograft transplant recipients. We will thus test the hypothesis that TKD-leukemia cells can switch between 'Progenitor-like proliferation' and 'Stem cell-like quiescence'. We are proposing four Aims to (1) validate BCL6 as therapeutic target in TKD-leukemia, (2) define mechanistic elements of BCL6-dependent drug-resistance, (3) validate and prioritize three different approaches of pharmacological inhibition of BCL6 and (4) develop a Phase I clinical trial for BCL6 inhibition in adults with relapse TKD-leukemia.